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Blood ; 110(12): 3959-67, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-17687108

ABSTRACT

Removal of pathogenic B lymphocytes by depletion of monoclonal antibodies (mAbs) or deprivation of B-cell survival factors has demonstrated clinical benefit in both oncologic and immunologic diseases. Partial clinical responses and emerging data demonstrating incomplete B-cell depletion after immunotherapy fuels the need for improved therapeutic modalities. Lessons from the first generation of therapeutics directed against B-cell-specific antigens (CD20, CD22) are being applied to develop novel antibodies with additional functional attributes. We describe the generation of a novel class of B-cell-directed therapy (anti-BR3 mAbs) that combines the depleting capacity of a therapeutic mAb and blockade of B-cell-activating factor (BAFF)-BR3 B-cell survival. In mice, treatment with antagonistic anti-BR3 antibodies results in quantitatively greater reduction in some B-cell subsets and qualitatively different effects on bone marrow plasma cells compared with BR3-Fc BAFF blockade or with anti-CD20 treatment. Comparative analysis of BR3-Fc and anti-BR3 mAb reveals a lower B-cell dependence for BAFF-mediated survival in nonhuman primates than in mice. This novel class of B-cell-targeted therapies shows species characteristics in mice and primates that will guide translation to treatment of human disease.


Subject(s)
Antibodies, Monoclonal/pharmacology , B-Cell Activation Factor Receptor/antagonists & inhibitors , Immune System Diseases/drug therapy , Immunotherapy , Lymphocyte Depletion , Neoplasms/drug therapy , Plasma Cells/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , B-Cell Activating Factor/antagonists & inhibitors , B-Cell Activating Factor/immunology , B-Cell Activation Factor Receptor/immunology , Bone Marrow Cells/immunology , Cell Survival/drug effects , Cell Survival/immunology , Immune System Diseases/immunology , Macaca fascicularis , Mice , Mice, Inbred BALB C , Neoplasms/immunology , Species Specificity
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